In contrast to HIV-1 infection i humans, HIV-1 infection in chimpanzees has traditionally been associated with an absence of disease development. A number of investigations have focused on determining the mechanisms of disease in this system. However, we have recently described the development of AIDS in a chimpanzee (C499) infected with HIV-1 for over ten year. The development of AIDS was associated with an increase in plasma viral loads and the presence of a virus which is highly cytopathic for chimpanzee peripheral blood mononuclear cells. In addition, transfusion of blood from C499 to an uninfected chimpanzee (C455) has resulted in the rapid and progressive decline of CD4 cells in the latter animal. To understand why C499 developed AIDS, this proposal focuses on two issues: a) the full characterization of the HIV-1 species derived from C499 and C455 so that specific pathogenic determinants can be identified; and b) a full determination of the mechanism of pathogenesis of this virus in vivo in newly-infected chimpanzees. It is hypothesized that specific genetic changes occurred over time in the virus present in C499 which fostered phenotypic adaptation for HIV-1 to the chimpanzee, resulting in the generation of a more pathogenic virus. We will elucidate the viral molecular determinants involved in the increased pathogenic effects of this HIV-1 isolate. Specific genes to be studied will include env, gag, and nef. The genetic findings will then be correlated with changes in biological activity of the virus including the ability to induce syncytium formation, macrophage tropism, and apoptosis induction. This will accomplished through detailed analysis of the parental virus and the use of chimeric molecular clones. Chimeric molecular clone construction will aid in the identification of important pathogenic determinants. In addition, we will generate full-length molecular clones of the virus isolated from C499 (termed HIV-1). Finally, based on preliminary results with C455, we hypothesize that HIV- 1 is pathogenic for chimpanzees and will cause AIDS in a much shorter time period. Thus, we propose to determine the mechanisms of pathogenesis of HIV-1 infection in chimpanzees (both uninfected and infected but both progressing), utilizing those animals originally designated as the HIV-1/chimpanzee cohort at the Yerkes Center in 1984. The infectious process in these animals will be examined in close detail (virus loads, immune responses (humoral and cellular), and lymph node pathogenesis) to evaluate an determine the mechanisms of pathogenesis of this highly virulent virus.